{"gene":"PSMD8","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1995,"finding":"Nin1p (yeast ortholog of PSMD8/p31) is a component of the 26S proteasome complex, as demonstrated by co-sedimentation with the 26S proteasome peak in glycerol density gradients after ATP-Mg2+ preincubation, and nin1-1 mutant cells accumulate polyubiquitinated proteins at restrictive temperatures, indicating a role in proteasome-dependent proteolysis.","method":"Glycerol density gradient fractionation, polyubiquitin accumulation assay, genetic analysis of cell cycle progression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, polyubiquitin accumulation, genetic epistasis with cdc28 alleles), foundational paper establishing proteasome membership","pmids":["7621825"],"is_preprint":false},{"year":1995,"finding":"Loss of Nin1p function causes synthetic lethality with certain cdc28 alleles and failure to activate Cdc28p (Cdk1) histone H1 kinase activity after release from G1 or S-phase arrest, placing Nin1p/PSMD8 upstream of Cdc28p activation via proteasome-dependent proteolysis.","method":"Genetic epistasis (synthetic lethality screen), histone H1 kinase activity assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with kinase activity readout, single lab, two orthogonal methods","pmids":["7621825"],"is_preprint":false},{"year":2000,"finding":"Fission yeast Mts3 (Rpn12/PSMD8 ortholog) physically binds Pus1 (Rpn10) in vitro, and the polyubiquitin-binding activity of Pus1 is essential for cell viability when Mts3 function is compromised (synthetic lethality of Δpus1 with mts3-1); overexpression of wild-type but not polyubiquitin-binding-deficient Pus1 rescues mts3-1, indicating functional cooperation between Rpn12 and Rpn10 in polyubiquitin substrate recognition.","method":"In vitro binding assay, genetic epistasis (synthetic lethality, overexpression rescue)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro binding combined with multiple genetic epistasis experiments demonstrating functional relationship between Rpn12 and Rpn10","pmids":["10809753"],"is_preprint":false},{"year":1999,"finding":"Genetic epistasis in yeast demonstrates that rpn12-1 (nin1-1) is synthetically lethal with rpt1-2, a mutation in the ATPase subunit Rpt1, placing Rpn12 in a functionally interacting relationship with the Rpt1 ATPase of the 19S base subparticle.","method":"Synthetic lethality screen, double-mutant analysis","journal":"Molecular & general genetics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis (synthetic lethality), single lab, single method","pmids":["10503546"],"is_preprint":false},{"year":2010,"finding":"S. pombe Rpn12 (PSMD8 ortholog) directly binds the UIM of Rpn10 in vitro with affinity comparable to Lys48-linked diubiquitin, as shown by NMR and crystallography, demonstrating that Rpn12 can compete with ubiquitin for Rpn10 UIM binding and thus potentially modulate Rpn10's activity as a proteasomal ubiquitin receptor.","method":"Crystal structure of Rpn10 vWA domain, NMR characterization of UIM–Rpn12 interaction, binding affinity measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus NMR with binding affinity quantification, single lab, two orthogonal structural/biophysical methods","pmids":["20739285"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of Rpn12 (PSMD8 ortholog) reveals a PCI-domain fold; mutagenesis of residues at a surface site impairs Rpn12 binding to Rpn10 in vitro and reduces Rpn10 incorporation into proteasomes in vivo, identifying the structural basis for Rpn12-mediated recruitment of the ubiquitin receptor Rpn10 to the 19S lid.","method":"Crystal structure determination, site-directed mutagenesis, in vitro binding assay, in vivo proteasome subunit incorporation assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis validated in both in vitro binding and in vivo incorporation assays, single lab, multiple orthogonal methods","pmids":["22906049"],"is_preprint":false},{"year":2020,"finding":"In C. elegans, RPN-12 (PSMD8 ortholog) null mutants lack sperm (feminized germline) without major loss of proteasome proteolytic activity; this phenotype is suppressed by downregulation of TRA-1, placing RPN-12 in the hermaphrodite germline sex determination pathway; RPN-12 loss also causes nuclear accumulation of meiotic kinase WEE-1.3 that is not reproduced by chemical proteasome inhibition, indicating a proteasome-independent or non-catalytic role for this subunit in WEE-1.3 localization.","method":"Null mutant analysis (rpn-12(av93)), RNAi epistasis, proteasome activity assay, protein localization imaging","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null mutant with epistasis and biochemical proteasome activity controls, single lab, multiple phenotypic readouts","pmids":["32767462"],"is_preprint":false},{"year":2020,"finding":"Backbone NMR resonance assignments of S. cerevisiae Rpn12 (PSMD8 ortholog) confirm it contains an N-terminal TPR-like domain and C-terminal WH domain, providing structural framework for understanding its interactions with other 19S subunits.","method":"NMR backbone resonance assignment","journal":"Biomolecular NMR assignments","confidence":"Low","confidence_rationale":"Tier 3 / Weak — NMR assignments alone without functional validation of interactions in same study","pmids":["32072453"],"is_preprint":false},{"year":2025,"finding":"Human PSMD8 directly interacts with and stabilizes SLC7A11 (a ferroptosis suppressor), negatively regulating ferroptosis but not apoptosis in bladder cancer cells; USP14 cooperates with PSMD8 to enhance SLC7A11 protein abundance; reduction of PSMD8 sensitizes bladder cancer cells to cisplatin.","method":"Co-immunoprecipitation (direct interaction), knockdown experiments with ferroptosis/apoptosis assays, protein stability assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct interaction by Co-IP and functional consequence shown by KD with specific ferroptosis readout, single lab, single study","pmids":["41403840"],"is_preprint":false}],"current_model":"PSMD8 (Rpn12/Nin1p) is an essential PCI-domain-containing lid subunit of the 19S regulatory particle of the 26S proteasome that recruits the ubiquitin receptor Rpn10 through a direct physical interaction involving its PCI domain surface, functionally cooperates with the base ATPase Rpt1, and in its human form directly interacts with and stabilizes SLC7A11 in cooperation with USP14 to suppress ferroptosis in cancer cells."},"narrative":{"mechanistic_narrative":"PSMD8 (Rpn12/Nin1p) is an essential subunit of the 19S regulatory particle of the 26S proteasome that links the regulatory particle to ubiquitin-dependent substrate recognition and proteolysis [PMID:7621825]. The protein adopts a PCI-domain fold whose surface site mediates recruitment of the ubiquitin receptor Rpn10 to the 19S lid; mutation of this surface impairs Rpn10 binding in vitro and reduces Rpn10 incorporation into proteasomes in vivo [PMID:22906049]. Structurally, PSMD8 directly engages the UIM of Rpn10 with an affinity comparable to Lys48-linked diubiquitin, allowing it to compete with ubiquitin for the Rpn10 receptor and thereby modulate substrate engagement [PMID:20739285]. This recruitment is functionally tied to polyubiquitin substrate recognition, as the polyubiquitin-binding activity of the Rpn10 ortholog becomes essential when PSMD8 function is compromised [PMID:10809753], and PSMD8 also functionally cooperates with the base ATPase Rpt1 [PMID:10503546]. Through its role in proteasome-dependent proteolysis, PSMD8 acts upstream of Cdc28/Cdk1 activation in cell cycle progression [PMID:7621825], and a null mutant studied in C. elegans further reveals a non-catalytic role independent of bulk proteasome proteolytic activity, affecting germline sex determination and nuclear localization of the meiotic kinase WEE-1.3 [PMID:32767462]. In human cancer cells, PSMD8 directly interacts with and stabilizes the ferroptosis suppressor SLC7A11 in cooperation with USP14, suppressing ferroptosis and modulating cisplatin sensitivity in bladder cancer [PMID:41403840].","teleology":[{"year":1995,"claim":"Established that PSMD8/Nin1p is a bona fide component of the 26S proteasome required for ubiquitin-dependent proteolysis, defining the molecular machine in which the protein operates.","evidence":"Glycerol density gradient co-sedimentation with the 26S peak and polyubiquitin accumulation in nin1-1 mutants in yeast","pmids":["7621825"],"confidence":"High","gaps":["Did not resolve which subparticle (base vs lid) the protein belongs to","No direct binding partners within the complex identified"]},{"year":1995,"claim":"Connected proteasome function via PSMD8 to cell cycle control by placing it upstream of Cdc28/Cdk1 activation.","evidence":"Synthetic lethality with cdc28 alleles and failure to activate Cdc28 histone H1 kinase activity in yeast","pmids":["7621825"],"confidence":"Medium","gaps":["Specific proteolytic substrate linking PSMD8 to Cdc28 activation not identified","Genetic interaction does not establish direct physical mechanism"]},{"year":1999,"claim":"Positioned PSMD8 in a functional relationship with the 19S base ATPase Rpt1, hinting at coordination between lid and base activities.","evidence":"Synthetic lethality of rpn12-1 with rpt1-2 in double-mutant analysis in yeast","pmids":["10503546"],"confidence":"Medium","gaps":["Single method (genetic) without biochemical demonstration of physical contact","Mechanism of Rpt1 cooperation unresolved"]},{"year":2000,"claim":"Demonstrated functional cooperation between PSMD8/Rpn12 and the ubiquitin receptor Rpn10 in polyubiquitin substrate recognition.","evidence":"In vitro binding of Mts3 to Pus1 and genetic synthetic lethality/overexpression rescue requiring Pus1 polyubiquitin-binding activity in fission yeast","pmids":["10809753"],"confidence":"High","gaps":["Structural basis of the interaction not yet defined","Whether interaction modulates or competes with ubiquitin binding unclear at this stage"]},{"year":2010,"claim":"Defined the biophysical nature of the PSMD8–Rpn10 interaction, showing it targets the Rpn10 UIM and can compete with ubiquitin.","evidence":"Crystal structure of Rpn10 vWA domain and NMR characterization of the UIM–Rpn12 interaction with affinity measurement in S. pombe","pmids":["20739285"],"confidence":"High","gaps":["Functional consequence of ubiquitin competition in vivo not measured","Did not define the PSMD8 surface mediating the contact"]},{"year":2012,"claim":"Identified the PCI-domain structural basis by which PSMD8 recruits Rpn10 into the 19S lid.","evidence":"Crystal structure of Rpn12, surface-site mutagenesis, in vitro binding and in vivo Rpn10 incorporation assays in yeast","pmids":["22906049"],"confidence":"High","gaps":["Dynamics of Rpn10 incorporation during proteasome assembly not resolved","Conservation of the surface site in human PSMD8 not tested"]},{"year":2020,"claim":"Revealed a proteasome-independent, non-catalytic role for PSMD8 in germline development and kinase localization, expanding its functions beyond bulk proteolysis.","evidence":"rpn-12 null mutant analysis, RNAi epistasis with tra-1, proteasome activity assays, and WEE-1.3 localization imaging in C. elegans","pmids":["32767462"],"confidence":"Medium","gaps":["Molecular mechanism for the non-catalytic effect on WEE-1.3 unknown","Whether this role generalizes beyond the worm germline untested"]},{"year":2020,"claim":"Provided NMR structural framework defining PSMD8 domain architecture (N-terminal TPR-like and C-terminal WH domains).","evidence":"NMR backbone resonance assignment of S. cerevisiae Rpn12","pmids":["32072453"],"confidence":"Low","gaps":["Assignments alone without functional validation of interactions in the same study","No interaction mapping derived from the assignments"]},{"year":2025,"claim":"Extended PSMD8 function to human cancer biology, showing it stabilizes the ferroptosis suppressor SLC7A11 and modulates chemosensitivity.","evidence":"Co-IP, knockdown with ferroptosis/apoptosis assays, and protein stability assays in bladder cancer cells; USP14 cooperation shown","pmids":["41403840"],"confidence":"Medium","gaps":["Single Co-IP-based study without reciprocal structural validation","Mechanism by which PSMD8 stabilizes SLC7A11 (proteasomal vs non-proteasomal) not resolved","Whether this is independent of canonical proteasome assembly role unclear"]},{"year":null,"claim":"How PSMD8's canonical proteasome-assembly/Rpn10-recruitment role mechanistically relates to its emerging non-catalytic substrate-stabilizing functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of human PSMD8 bound to SLC7A11","Whether SLC7A11 stabilization requires intact 26S proteasome unknown","Direct ubiquitin-receptor recruitment role in human cells untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,5]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,5]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]}],"complexes":["26S proteasome","19S regulatory particle (lid)"],"partners":["PSMD4","PSMC2","SLC7A11","USP14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48556","full_name":"26S proteasome non-ATPase regulatory subunit 8","aliases":["26S proteasome regulatory subunit RPN12","26S proteasome regulatory subunit S14","p31"],"length_aa":350,"mass_kda":39.6,"function":"Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P48556/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD8","classification":"Common Essential","n_dependent_lines":984,"n_total_lines":1208,"dependency_fraction":0.8145695364238411},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMC4","stoichiometry":10.0},{"gene":"ECPAS","stoichiometry":0.2},{"gene":"PSMD10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PSMD8","total_profiled":1310},"omim":[{"mim_id":"617844","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 8; PSMD8","url":"https://www.omim.org/entry/617844"},{"mim_id":"300540","title":"HAUS AUGMIN-LIKE COMPLEX, SUBUNIT 7; HAUS7","url":"https://www.omim.org/entry/300540"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":667.0}],"url":"https://www.proteinatlas.org/search/PSMD8"},"hgnc":{"alias_symbol":["S14","Nin1p","p31","HIP6","HYPF","Rpn12"],"prev_symbol":[]},"alphafold":{"accession":"P48556","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48556","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48556-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48556-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD8","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD8"},"sequence":{"accession":"P48556","fasta_url":"https://rest.uniprot.org/uniprotkb/P48556.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48556/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48556"}},"corpus_meta":[{"pmid":"11714922","id":"PMC_11714922","title":"Solution conditions can promote formation of either amyloid protofilaments or mature fibrils from the HypF 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Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/11856843","citation_count":5,"is_preprint":false},{"pmid":"23911865","id":"PMC_23911865","title":"Effect of osmolytes on the fibrillation of HypF-N.","date":"2013","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/23911865","citation_count":3,"is_preprint":false},{"pmid":"39544425","id":"PMC_39544425","title":"Protein profile changes during priming explants to embryogenic response in Coffea canephora: identification of the RPN12 proteasome subunit involved in the protein degradation.","date":"2024","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/39544425","citation_count":2,"is_preprint":false},{"pmid":"19409514","id":"PMC_19409514","title":"Proteomic analysis of cells exposed to prefibrillar aggregates of HypF-N.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19409514","citation_count":2,"is_preprint":false},{"pmid":"29786756","id":"PMC_29786756","title":"Backbone NMR assignments of HypF-N under conditions generating toxic and non-toxic oligomers.","date":"2018","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/29786756","citation_count":1,"is_preprint":false},{"pmid":"41403840","id":"PMC_41403840","title":"PSMD8 cooperates with USP14 to promote bladder cancer progression by inhibiting ferroptosis.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41403840","citation_count":0,"is_preprint":false},{"pmid":"32072453","id":"PMC_32072453","title":"Backbone 1H, 13C and 15N resonance assignments of the proteasome lid subunit Rpn12 from Saccharomyces cerevisiae.","date":"2020","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/32072453","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.14.24317129","title":"Comprehensive analysis of key m6A RNA modification-related genes and immune infiltrates in hypertrophic cardiomyopathy","date":"2024-11-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.14.24317129","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.30.605947","title":"IDENTIFICATION OF IMMUNE RESPONSE AND RNA NETWORK OF RHEUMATOID ARTHRITIS AND MOLECULAR DOCKING OF  <i>CELASTRUS PANICULATUS</i>  AS POTENTIAL THERAPEUTIC AGENT","date":"2024-08-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.30.605947","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22042,"output_tokens":2274,"usd":0.050118,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9347,"output_tokens":3311,"usd":0.064755,"stage2_stop_reason":"end_turn"},"total_usd":0.114873,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Nin1p (yeast ortholog of PSMD8/p31) is a component of the 26S proteasome complex, as demonstrated by co-sedimentation with the 26S proteasome peak in glycerol density gradients after ATP-Mg2+ preincubation, and nin1-1 mutant cells accumulate polyubiquitinated proteins at restrictive temperatures, indicating a role in proteasome-dependent proteolysis.\",\n      \"method\": \"Glycerol density gradient fractionation, polyubiquitin accumulation assay, genetic analysis of cell cycle progression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, polyubiquitin accumulation, genetic epistasis with cdc28 alleles), foundational paper establishing proteasome membership\",\n      \"pmids\": [\"7621825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Loss of Nin1p function causes synthetic lethality with certain cdc28 alleles and failure to activate Cdc28p (Cdk1) histone H1 kinase activity after release from G1 or S-phase arrest, placing Nin1p/PSMD8 upstream of Cdc28p activation via proteasome-dependent proteolysis.\",\n      \"method\": \"Genetic epistasis (synthetic lethality screen), histone H1 kinase activity assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with kinase activity readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"7621825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Fission yeast Mts3 (Rpn12/PSMD8 ortholog) physically binds Pus1 (Rpn10) in vitro, and the polyubiquitin-binding activity of Pus1 is essential for cell viability when Mts3 function is compromised (synthetic lethality of Δpus1 with mts3-1); overexpression of wild-type but not polyubiquitin-binding-deficient Pus1 rescues mts3-1, indicating functional cooperation between Rpn12 and Rpn10 in polyubiquitin substrate recognition.\",\n      \"method\": \"In vitro binding assay, genetic epistasis (synthetic lethality, overexpression rescue)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro binding combined with multiple genetic epistasis experiments demonstrating functional relationship between Rpn12 and Rpn10\",\n      \"pmids\": [\"10809753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Genetic epistasis in yeast demonstrates that rpn12-1 (nin1-1) is synthetically lethal with rpt1-2, a mutation in the ATPase subunit Rpt1, placing Rpn12 in a functionally interacting relationship with the Rpt1 ATPase of the 19S base subparticle.\",\n      \"method\": \"Synthetic lethality screen, double-mutant analysis\",\n      \"journal\": \"Molecular & general genetics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis (synthetic lethality), single lab, single method\",\n      \"pmids\": [\"10503546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S. pombe Rpn12 (PSMD8 ortholog) directly binds the UIM of Rpn10 in vitro with affinity comparable to Lys48-linked diubiquitin, as shown by NMR and crystallography, demonstrating that Rpn12 can compete with ubiquitin for Rpn10 UIM binding and thus potentially modulate Rpn10's activity as a proteasomal ubiquitin receptor.\",\n      \"method\": \"Crystal structure of Rpn10 vWA domain, NMR characterization of UIM–Rpn12 interaction, binding affinity measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus NMR with binding affinity quantification, single lab, two orthogonal structural/biophysical methods\",\n      \"pmids\": [\"20739285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of Rpn12 (PSMD8 ortholog) reveals a PCI-domain fold; mutagenesis of residues at a surface site impairs Rpn12 binding to Rpn10 in vitro and reduces Rpn10 incorporation into proteasomes in vivo, identifying the structural basis for Rpn12-mediated recruitment of the ubiquitin receptor Rpn10 to the 19S lid.\",\n      \"method\": \"Crystal structure determination, site-directed mutagenesis, in vitro binding assay, in vivo proteasome subunit incorporation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis validated in both in vitro binding and in vivo incorporation assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22906049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In C. elegans, RPN-12 (PSMD8 ortholog) null mutants lack sperm (feminized germline) without major loss of proteasome proteolytic activity; this phenotype is suppressed by downregulation of TRA-1, placing RPN-12 in the hermaphrodite germline sex determination pathway; RPN-12 loss also causes nuclear accumulation of meiotic kinase WEE-1.3 that is not reproduced by chemical proteasome inhibition, indicating a proteasome-independent or non-catalytic role for this subunit in WEE-1.3 localization.\",\n      \"method\": \"Null mutant analysis (rpn-12(av93)), RNAi epistasis, proteasome activity assay, protein localization imaging\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null mutant with epistasis and biochemical proteasome activity controls, single lab, multiple phenotypic readouts\",\n      \"pmids\": [\"32767462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Backbone NMR resonance assignments of S. cerevisiae Rpn12 (PSMD8 ortholog) confirm it contains an N-terminal TPR-like domain and C-terminal WH domain, providing structural framework for understanding its interactions with other 19S subunits.\",\n      \"method\": \"NMR backbone resonance assignment\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — NMR assignments alone without functional validation of interactions in same study\",\n      \"pmids\": [\"32072453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human PSMD8 directly interacts with and stabilizes SLC7A11 (a ferroptosis suppressor), negatively regulating ferroptosis but not apoptosis in bladder cancer cells; USP14 cooperates with PSMD8 to enhance SLC7A11 protein abundance; reduction of PSMD8 sensitizes bladder cancer cells to cisplatin.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction), knockdown experiments with ferroptosis/apoptosis assays, protein stability assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct interaction by Co-IP and functional consequence shown by KD with specific ferroptosis readout, single lab, single study\",\n      \"pmids\": [\"41403840\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD8 (Rpn12/Nin1p) is an essential PCI-domain-containing lid subunit of the 19S regulatory particle of the 26S proteasome that recruits the ubiquitin receptor Rpn10 through a direct physical interaction involving its PCI domain surface, functionally cooperates with the base ATPase Rpt1, and in its human form directly interacts with and stabilizes SLC7A11 in cooperation with USP14 to suppress ferroptosis in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMD8 (Rpn12/Nin1p) is an essential subunit of the 19S regulatory particle of the 26S proteasome that links the regulatory particle to ubiquitin-dependent substrate recognition and proteolysis [#0]. The protein adopts a PCI-domain fold whose surface site mediates recruitment of the ubiquitin receptor Rpn10 to the 19S lid; mutation of this surface impairs Rpn10 binding in vitro and reduces Rpn10 incorporation into proteasomes in vivo [#5]. Structurally, PSMD8 directly engages the UIM of Rpn10 with an affinity comparable to Lys48-linked diubiquitin, allowing it to compete with ubiquitin for the Rpn10 receptor and thereby modulate substrate engagement [#4]. This recruitment is functionally tied to polyubiquitin substrate recognition, as the polyubiquitin-binding activity of the Rpn10 ortholog becomes essential when PSMD8 function is compromised [#2], and PSMD8 also functionally cooperates with the base ATPase Rpt1 [#3]. Through its role in proteasome-dependent proteolysis, PSMD8 acts upstream of Cdc28/Cdk1 activation in cell cycle progression [#1], and a null mutant studied in C. elegans further reveals a non-catalytic role independent of bulk proteasome proteolytic activity, affecting germline sex determination and nuclear localization of the meiotic kinase WEE-1.3 [#6]. In human cancer cells, PSMD8 directly interacts with and stabilizes the ferroptosis suppressor SLC7A11 in cooperation with USP14, suppressing ferroptosis and modulating cisplatin sensitivity in bladder cancer [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that PSMD8/Nin1p is a bona fide component of the 26S proteasome required for ubiquitin-dependent proteolysis, defining the molecular machine in which the protein operates.\",\n      \"evidence\": \"Glycerol density gradient co-sedimentation with the 26S peak and polyubiquitin accumulation in nin1-1 mutants in yeast\",\n      \"pmids\": [\n        \"7621825\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve which subparticle (base vs lid) the protein belongs to\",\n        \"No direct binding partners within the complex identified\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Connected proteasome function via PSMD8 to cell cycle control by placing it upstream of Cdc28/Cdk1 activation.\",\n      \"evidence\": \"Synthetic lethality with cdc28 alleles and failure to activate Cdc28 histone H1 kinase activity in yeast\",\n      \"pmids\": [\n        \"7621825\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific proteolytic substrate linking PSMD8 to Cdc28 activation not identified\",\n        \"Genetic interaction does not establish direct physical mechanism\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Positioned PSMD8 in a functional relationship with the 19S base ATPase Rpt1, hinting at coordination between lid and base activities.\",\n      \"evidence\": \"Synthetic lethality of rpn12-1 with rpt1-2 in double-mutant analysis in yeast\",\n      \"pmids\": [\n        \"10503546\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single method (genetic) without biochemical demonstration of physical contact\",\n        \"Mechanism of Rpt1 cooperation unresolved\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated functional cooperation between PSMD8/Rpn12 and the ubiquitin receptor Rpn10 in polyubiquitin substrate recognition.\",\n      \"evidence\": \"In vitro binding of Mts3 to Pus1 and genetic synthetic lethality/overexpression rescue requiring Pus1 polyubiquitin-binding activity in fission yeast\",\n      \"pmids\": [\n        \"10809753\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the interaction not yet defined\",\n        \"Whether interaction modulates or competes with ubiquitin binding unclear at this stage\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the biophysical nature of the PSMD8–Rpn10 interaction, showing it targets the Rpn10 UIM and can compete with ubiquitin.\",\n      \"evidence\": \"Crystal structure of Rpn10 vWA domain and NMR characterization of the UIM–Rpn12 interaction with affinity measurement in S. pombe\",\n      \"pmids\": [\n        \"20739285\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of ubiquitin competition in vivo not measured\",\n        \"Did not define the PSMD8 surface mediating the contact\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the PCI-domain structural basis by which PSMD8 recruits Rpn10 into the 19S lid.\",\n      \"evidence\": \"Crystal structure of Rpn12, surface-site mutagenesis, in vitro binding and in vivo Rpn10 incorporation assays in yeast\",\n      \"pmids\": [\n        \"22906049\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Dynamics of Rpn10 incorporation during proteasome assembly not resolved\",\n        \"Conservation of the surface site in human PSMD8 not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a proteasome-independent, non-catalytic role for PSMD8 in germline development and kinase localization, expanding its functions beyond bulk proteolysis.\",\n      \"evidence\": \"rpn-12 null mutant analysis, RNAi epistasis with tra-1, proteasome activity assays, and WEE-1.3 localization imaging in C. elegans\",\n      \"pmids\": [\n        \"32767462\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism for the non-catalytic effect on WEE-1.3 unknown\",\n        \"Whether this role generalizes beyond the worm germline untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided NMR structural framework defining PSMD8 domain architecture (N-terminal TPR-like and C-terminal WH domains).\",\n      \"evidence\": \"NMR backbone resonance assignment of S. cerevisiae Rpn12\",\n      \"pmids\": [\n        \"32072453\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Assignments alone without functional validation of interactions in the same study\",\n        \"No interaction mapping derived from the assignments\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended PSMD8 function to human cancer biology, showing it stabilizes the ferroptosis suppressor SLC7A11 and modulates chemosensitivity.\",\n      \"evidence\": \"Co-IP, knockdown with ferroptosis/apoptosis assays, and protein stability assays in bladder cancer cells; USP14 cooperation shown\",\n      \"pmids\": [\n        \"41403840\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP-based study without reciprocal structural validation\",\n        \"Mechanism by which PSMD8 stabilizes SLC7A11 (proteasomal vs non-proteasomal) not resolved\",\n        \"Whether this is independent of canonical proteasome assembly role unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMD8's canonical proteasome-assembly/Rpn10-recruitment role mechanistically relates to its emerging non-catalytic substrate-stabilizing functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of human PSMD8 bound to SLC7A11\",\n        \"Whether SLC7A11 stabilization requires intact 26S proteasome unknown\",\n        \"Direct ubiquitin-receptor recruitment role in human cells untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0060090\",\n        \"supporting_discovery_ids\": [\n          2,\n          4,\n          5\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [\n          0,\n          5\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0000502\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-392499\",\n        \"supporting_discovery_ids\": [\n          0,\n          2\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-1640170\",\n        \"supporting_discovery_ids\": [\n          1\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle (lid)\"\n    ],\n    \"partners\": [\n      \"PSMD4\",\n      \"PSMC2\",\n      \"SLC7A11\",\n      \"USP14\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}